Project Summary/Abstract Globally, millions of people suffer loss of vision as a result of injury, degeneration, or improperly formed neural circuitry within the visual system. While there are many efforts to regenerate inputs to the visual cortex, any successful therapy must include the integration of new inputs into existing cortical circuitry. During normal visual development, this occurs as a result of heightened sensory plasticity during a limited time window, referred to as a critical period. It is not understood how critical period plasticity can be re-opened in adulthood for effective therapeutic strategies. Furthermore, inhibition and cholinergic modulation are known components of critical period plasticity but have yet to be linked. My preliminary data demonstrates a common pathway for these mechanisms: out of the major inhibitory interneuron groups, only somatostatin-expressing (SST) interneurons undergo a reversal in their response during attentive vision at the closure of the critical period. While it is known that SST interneurons mediate pyramidal cell dendritic activity during attention in adults, it is not known how cholinergic inputs are directly acting on SST interneurons to alter dendritic activity during critical period plasticity. My working hypothesis is that the shift in modulation of SST cells alters dendritic learning rules to close the critical period. Here I am proposing two specific aims to address the challenge of re- establishing strong plasticity in the adult cortex. In Aim 1, in order to understand how cholinergic inputs may be changing in the transition to adulthood, I will test cholinergic inputs to SST interneurons across age groups using channelrhodopsin-assisted circuit mapping. In Aim 2, I will use in vivo two-photon microscopy to compare normal SST responses to those seen in mice lacking a cholinergic receptor antagonist, Lynx1, which is an essential component for critical period closure. These aims should advance a circuit-level understanding of how plasticity becomes limited in adulthood and will inform novel therapeutic strategies for visual disorders.